DESCRIPTION (Verbatim from the Applicant's Abstract): The long-term goal is advancement of dynamic-contrast-enhanced [bolus-tracking (B-T)] MRI - the high (time/space) resolution recording of contrast reagent (CR) passage following bolus injection. Though applied to all tissues, the low-MW Gd(111) chelates are particularly good probes for blood-brain-barrier (BBB) integrity. Even slight compromises of the para(endothelial)cellular pathway defining BBB tightness are detected. Basic B-T pharmacokinetic parameters (CR as tracer) measure: a) perfusion CR delivery, b) capillary wall CR permeability, and c) CR-accessible (interstitial) space. These lead to efficacious B-T studies of multiple sclerosis (MS) white matter (WM) lesions and brain tumors. The usual determination of concentration, [CR], from a linear relationship with the measured longitudinal tissue 'H2O relaxation time (T') reciprocal requires the fast exchange limit (FXL) for equilibrium transcytolemmal water exchange. But, new results show that (though fast) the system departs the FXL at very low tissue [CR]s (<100 I1M). Two-site-exchange (2SX) modeling accounts for this and leads to important conclusions: 1) at clinical fields [< 2 T] most used, it is very difficult to detect CR before the system has departed the FXL and large [CR] errors result assuming it, II) at higher fields (4 T here), the T, and S/N increase allow CR detection at low levels (easily 5 I1M tissue [CR]) sufficient to insure the FXL, 111) time courses of real (thermodynamic) interstitial [CR] (directly from 2SX) and plasma [CR] ("input function" from a great vessel) allow the factorization of all three pharmacokinetic parameters not possible with a single traditional tracer. Three specific aims extend these findings to quantitative 4 T investigations ( about3 mm3) of: 1) the normal human brain, 2) normal-appearing regions of MS brains, and 3) MS lesions. In normal brain, one detects sufficiently low CR to observe actual WM uptake after a standard dose (0.1 mmol/kg), heretofore thought not possible with MRI CRs. Moreover, the FXL obtains, and an additional early time course contribution from equilibrium trans-BBB water exchange allows 2SX modeling with an ROI blood volume parameter facilitating further factoring the perfusion parameter into volume and velocity contributions. Despite a doubled BBB permeability in normal-appearing WM of MS brains, the system remains in the FXL. With the increased CR uptake in MS lesion rims, the system greatly departs the FXL after a standard dose. High 4 T sensitivity permits restudying the same lesion at an ultra-low dose (possibly 0.01 mmol/kg) sufficient for the FXL. Fitting both data sets yields a new parameter measuring the ROI average transcytolemmal water permeability coefficient. This work involves aspects of physics, physical chemistry, biophysics, physiology (all normal tissues), and relates to a number of pathologies including MS and cancer.